Slow tight binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen

Eleanor Jing Yi Cheong, Pramod C. Nair, Rebecca Wan Yi Neo, Ho Thanh Tu, Fu Lin, Edmund Chiong, Kesavan Esuvaranathan, Hao Fan, Russell Szmulewitz, Cody J. Peer, William D. Figg, Christina Li Lin Chai, John O. Miners, Eric Chun Yong Chan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki* = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of −14.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, in which equipotent reduction of downstream plasma DHEA-sulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden.

    SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.

    Original languageEnglish
    Pages (from-to)438-451
    Number of pages14
    JournalThe Journal of pharmacology and experimental therapeutics
    Volume374
    Issue number3
    DOIs
    Publication statusPublished - 1 Sep 2020

    Keywords

    • androgen
    • anticancer agents
    • cancer
    • CYP inhibition
    • cytochrome P450
    • molecular dynamics
    • pharmacokinetic / pharmacodynamic modeling
    • SA

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